This invention relates to stents for angioplasty, and in particular, relates to a device adapted to convey radioactive agents.
The term xe2x80x9cstentxe2x80x9d is intended to indicate devices intended for endoluminal application (e.g., within a blood vessel), normally fitted via catheterization, with subsequent deployment in situ so as to provide a local supporting effect for the lumen.
For a general review of vascular stents reference may usefully be made to the work xe2x80x9cTextbook of Interventional Cardiologyxe2x80x9d by Eric J. Topol, W. B. Saunders Company, 1994, and in particular section IV of Volume II entitled xe2x80x9cCoronary stentingxe2x80x9d. A large number of patent documents have also been devoted to the subject, as evidenced by, for example, EP-A-0 806 190, EP-A-0 850 604, EP-A-0 847 766, EP-A-0 857 470, EP-A-0 875 215, EP-A-0 895 759 and EP-A-0 895 760.
Clinical use of such devices, which has developed appreciably in the course of the last few years, has to meet the need to ensure an effective action to counter the phenomenon currently known as restenosis. This is the phenomenon, associated with physiological mechanisms which are not yet wholly clear, as a result of which the site of the stenosis which is reopened through the effect of the stent implant tends gradually to close again, generally through the effect of gradual tissue growth.
Various arrangements that provide for developing an effect at local level which counters the phenomena giving rise to restenosis have been proposed in order to deal with this problem. In particular, various arrangements that provide for the local release of drugs or the local use of radioactive sources have been investigated. Arrangements based on local controlled release of drugs must, as a primary requirement, overcome the problem of effectively ensuring location at the site of the stent implant.
Arrangements that provide for the use of radioactive sources face a variety of difficulties. The main problems associated with the use of radioactive materials to counter restenosis are associated with distribution of the dose in the tissue and its decay over time. There are no radioisotopes having at the same time an energy and a type of radiation that can provide a uniform and effective dose in the first few millimeters of the wall but negligible at greater depths, a sufficiently long half-life to enable the radioisotope to be stored for a reasonable period of time (e.g., weeks) but which is sufficiently short not to permanently damage the vessel into which it is implanted; very high specific activity, and optimum biocompatibility.
However, there are partial solutions to the above problems. For example, phosphorus 32 has good characteristics in terms of half-life. Phosphorus 32 also can be obtained with high specific activities and can be implanted on the surface of the stent, but has low penetration (14 days, 1.7 MeV beta radiation). Palladium 103 has good half-life and penetration properties (17 days, 20 keV X-rays), but its specific activity is very low. Nevertheless, the use of enriched palladium obtained by irradiation in a reactor or through cyclotron irradiation starting from rhodium and performing a chemical separation have been suggested. The main disadvantage of this arrangement is in the relatively high cost of the material so obtained. Yttrium 90 has good penetration properties, but decays very quickly (64 hours, 2.2 MeV beta radiation). It has therefore been suggested that yttrium should be deposited on the stent a few hours before implantation, but this arrangement has appreciable problems and the possible effects in terms of biocompatibility have not yet been entirely clarified. Ruthenium 106 has excellent properties in terms of penetration, but lasts too long (1 year, 3.5 MeV beta radiation). Other radioisotopes, such as silver 105, have properties similar to palladium 103, and the same problems.
It can be said however, that the materials which are likely to have valuable properties with regard to having an effect which counters restenosis are poorly suitable, or not at all suitable, for producing the stent or parts thereof.
In every case the fact that the stent is rendered radioactive produces difficulties of a logistical type (implantation of the stent and the corresponding preparatory work are in fact of the nature of nuclear medicine activities), or unsatisfactory performance from the point of view of radioactive behavior.
The above-mentioned difficulties may perhaps explain why this research and investigation work has not yet resulted in effectively wide use of the corresponding methods. This irrespective of the fact that there is quite a large number of patent documents relating to the application of materials, in particular radioactive materials having an action which counters restenosis onto stents, or techniques substantially similar thereto. Among these documents, in addition to documents such as U.S. Pat. Nos. 5,059,166 (Fischell et al.); 5,176,617 (Fischell et al.) and 5,213,561 (Weinstein et al.) relating to the construction of radioactive stents, mention may be made of U.S. Pat. Nos. 5,722,984 (Fischell et al.), 5,840,009 (Klein et al.) and 5,605,530 (Fischell et al.) which refer to the application of substances such as phosphorylcholine labeled with phosphorus 32 to a stent, or means for overcoming the weakening of the dose at the ends of the stent through adding phosphorus 32 to the ends thereof, or again providing a screen to avoid the adverse effects of irradiation at the time when the stent is implanted.
Other documents such as WO-A-98/43694, WO-A-99/02195 or WO-A-99/09912 relate to coating a stent (or other means) with an antigen with a view to subsequent injection of a radioactive antibody, the application of a layer of radio-opaque material designed to receive the ionic implantation of radioactive material, or again a method of local treatment actuated by a device similar to a stent coated with a substance which is capable of reacting with another substance administered orally to generate in the locality a third substance which has a therapeutic effect.
U.S. Pat. No. 5,779,732 (Amundson) illustrates how a sheet of plastic containing a releasable substance can be located around a stent, while EP-A-0 873 732 discloses a stent coated with a substance which attracts heparin to form a layer of heparin.
Covering the wall of a vessel with an adhesive substance which is also radioactive is known from U.S. Pat. No. 5,873,811 (Wang et al.), while U.S. Pat. Nos. 5,871,436 (Eury) and 5,843,163 (Wall) describe how a radioactive substance can be fixed by means of a specific chelating agent or the use of a wire of radioactive material to keep an apertured stent extended.
WO-A-98/48851 teaches how a radioisotope can be applied to a metal stent: a very great number of isotopes are considered and the stents are of steel or shape memory metal (such as that sold under the trade designation xe2x80x9cNitinolxe2x80x9d). Methods of application are electrochemical, of the electrodeless type, using peptides, fats or thiols. Yet other documents refer to brachytherapy techniques using radioactive sources temporarily located within the vessel: for example U.S. Pat. Nos. 5,865,720 (Hastings et al.) and 5,840,008 (Klein et al.) teach how a type of radioactive sheath or sleeve can be placed around a balloon. Furthermore, U.S. Pat. No. 5,707,332 (Weinberger) examines in detail all possible radioisotopes which could be used for brachytherapy, but finds none to be ideal. A source (liquid or gas) which is to be placed in the balloon, or a wire source which is moved forward and backwards in order to provide treatment as desired, is described.
This invention is a device or envelope for conveying a radioactive agent to a stenotic site. The envelope according to this invention can be applied to virtually any kind of stent, independently of, for example, the shape, type, technology of construction and method of expansion (balloon catheter, shape-memory, etc.) of the stent itself and can be constructed using a variety of techniques depending upon the radioactive agent delivered and/or the performance required. Both the materials and the dimensions, and in particular the length, of the envelope are wholly independentxe2x80x94and may therefore also be markedly differentxe2x80x94from the corresponding characteristics of the stent. For example, the envelope may be made to be shorter (or longer) than the stent, if this corresponds to an application requirement.
The device of this invention therefore makes both the choice and the method of dosing the radioactive agent wholly independent of the characteristics of the stent. In particular the choice of radioactive agent can be optimized and/or different doses of radioactive agent can be used in different parts of the stent. With the arrangement according to the invention it is even possible to deliver several different radioactive agents to one stent, for example to achieve different radiation characteristics in different areas of the stent and/or at different times following implantation of the stent.
A basic feature is provided by the fact that the arrangement according to the invention makes it possible to activate only the radioactive agent which has been delivered (at most together with the means delivering it), thus avoiding it being necessary to activate the stent itself, even in part.
The latter advantage is valuable for at least two reasons. First, the invention makes it possible to avoid activating the material comprising the stent. Usually activation of the stent as a whole gives rise to radiation phenomena which are difficult to control in relation to both dosage and the properties of the activated isotopes, and again in that it gives rise to mixed radiation resulting from various isotopes contained in the material forming the stent. Second, the device according to the invention is in fact capable of being associated with the stent only at the time of implantation and before such time may therefore follow a cycle of production, activation (usually by irradiation) and storage before and after activation which is wholly independent of the cycle for the production, distribution and storage of the stent.
In particular, the latter should not at any time be subjected to constraints imposed by the handling of radioactive material. All this with the further important advantage conferred by the fact that when a period of time has lapsed after activation of the device such that it can be considered that it has lost the desired level of radioactivity, only the device, and not, as is the case with traditional arrangements, the stent as well, and, furthermore, the introduction kit (balloon catheter, etc.) associated with it, need to be subjected to disposal. Above all, the arrangement according to the invention is also suitable for possible treatment to reactivate the device when this has lost its desired radioactive properties.
In one aspect, this invention is a device for conveying a radioactive agent onto a stent having a longitudinal axis and an inner surface and an outer surface, the stent being capable of being dilated from a radially-contracted position to a radially-expanded position, the device comprising a body portion having a longitudinal axis and an inner surface and an outer surface, the body portion configured to be disposed such that one of the inner and outer surfaces of the body portion is adjacent one of the inner and outer surfaces of the stent and capable of being dilated upon delivery of the stent at the stenotic site, the body portion comprising a material adapted to convey an effective amount of the radioactive agent to the stenotic site. The radioactive agent may be yttrium 90 and may be distributed non-uniformly within a matrix. The body portion preferably has a generally tubular shape. The body portion may comprise wire, and the wire may have a variable diameter. The body portion may be a sheet wound into a spiral, or it may have an apertured or reticular structure. Preferably, the inner surface of the body portion fits over the outer surface of the stent. The radioactive agent may comprise multiple components and may be in a particulate form, such as nanoparticles, within the matrix. The matrix may comprise fibers and/or may be erodible to permit gradual release of the radioactive material.
In a second aspect, this invention is a method of delivering a radioactive agent to a stenotic site comprising providing a stent having a longitudinal axis, an inner surface and an outer surface, the stent being capable of being dilated from a radially-contracted position to a radially-expanded position; providing a device comprising a body portion having a longitudinal axis and an inner surface and an outer surface, the body portion configured to be disposed such that a surface of the body portion is adjacent a surface of the stent and capable of being dilated upon delivery of the stent at the stenotic site, the body portion comprising a material adapted to convey an effective amount of the radioactive agent to the stenotic site; advancing the stent and the device through a patient""s vasculature to the site of stenosis; and dilating the stent and the device at the site of stenosis such that a surface of the body portion of the device is positioned adjacent a surface of the stent. The dilating step may comprise positioning the surface of the body portion of the device adjacent the outer surface of the stent. The stent may be formed from a tubular blank.
In a third aspect, this invention is a kit for conveying a radioactive agent onto a stent having a longitudinal axis and an inner surface and an outer surface, the stent being capable of being dilated from a radially-contracted position to a radially-expanded position, the kit comprising a device comprising a body portion having a longitudinal axis and an inner surface and an outer surface, the body portion configured to be disposed such that one of the surfaces of the body portion is adjacent a surface of the stent and capable of being dilated upon delivery of the stent at the stenotic site, the body portion comprising a material adapted to convey an effective amount of the radioactive agent to the stenotic site; and a container configured to house the device. The kit may further comprise the stent and a catheter adapted to deliver the stent and the device to the site of restenosis.